JPH06271576A - Manufacturing of imidazole derivative - Google Patents

Abstract

PURPOSE: To obtain derivs. effectively in a high yield, excellent in selectivity and useful for the intermediates of medicines for hypertension, glaucoma etc., by reacting diimide with a specified compd.

CONSTITUTION: The objective derivs. of formula III are obtained by reacting the compds. represented by formula I [where R¹ is H, lower alkyl, -CF₃ or the like; R is H or the group of formula II (X¹-X³ are each H, halogen, lower alkyl or the like) or the like; R²-R⁵ are each H, lower alkyl or the like, R¹³-R¹⁸ are each H, lower alkyl, lower fluoroalkyl or the like] with diimide (HN=NH).

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an imidazole derivative. In particular, the present invention relates to a method for producing an imidazole derivative and intermediates thereof useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like.

[0002]

2. Description of the Related Art The present inventors have focused on angiotensin II antagonists as prophylactic / therapeutic agents for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia, etc. As a result of extensive studies on active compounds, which have a rapid onset of action when injected intravenously, have good absorption and transfer into the body when orally administered, have low toxicity, and have a long duration of action, :

[Chemical 9] A new imidazole derivative having a hydrazine bridged structure represented by
277537, Japanese Patent Application No. 3-323474, Japanese Patent Application 4-0
95191, Japanese Patent Application No. 4-216809).

In the method for producing the above imidazole compound,
When reducing the C ring double bond of a compound produced by the Diels Alder reaction (see the reaction route below), especially when R is a protecting group such as benzyl group, deprotection reaction such as debenzylation It is common to carry out the reduction reaction in a hydrogen gas atmosphere in methanol using a palladium hydroxide catalyst that simultaneously enables the above. However, in this reduction reaction, the compound (1) in which the C ring represented by -P- forms a bicyclo group, depending on the type and size of the R ¹³ group or R ¹⁷ group and the reaction conditions, In addition to the compound (2) described above, 10 to 60% of the ring-opened product (3) is produced as a by-product, so purification by column chromatography is indispensable, and the yield is never satisfactory. However, there was a problem in economic efficiency as a process of mass synthesis.

[0004]

[Chemical 10]

In addition, in this side reaction, the following π
It is possible that the formation of the -allyl-palladium complex is involved. However, a similar side reaction was observed when platinum oxide and palladium carbon were used instead of palladium hydroxide, and the details thereof have not been clarified yet. In addition, it was found that this side reaction hardly occurs with the Lindlar catalyst, but the target reaction may not proceed, possibly due to impurities contained in the raw materials during large-scale synthesis, and there is a problem in terms of reproducibility. It was

[0006]

[Chemical 11]

[0007]

The object of the present invention is to reduce the C-ring double bond in the imidazole derivative in order to achieve a high yield even in large-scale synthesis and to eliminate the need for a complicated purification step. It is to improve selectivity.

[0008]

Means for Solving the Problems The inventors of the present invention have made extensive studies in order to solve the above problems, and as a result, by reacting a C-containing imidazole compound with a diimide (HN = NH), the C ring is cleaved. It was found that the C ring double bond can be selectively reduced without reaction, and the present invention has been completed.

That is, the present invention has the general formula (I):

[Chemical 12] [Wherein R ¹ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a lower alkenyl group, a —CF ₃ group, an aryl group or an aralkyl group; R is a hydrogen atom, or A group selected from the group shown:

[Chemical 13] Here, X is —CH ₂ —, —NR′—, an oxygen atom or —
S (O) _n - represents, here, R 'is a hydrogen atom or a lower alkyl group, here, n represents 0, 1 or 2; here, X ^1,
X ² and X ³ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group,
Cyano group, 1H-tetrazol-5-yl group or alkali metal salts thereof, -CO ₂ R ⁷ group, -CONR'R "group,
-CONHSO ₂ R ⁸ group, an amino group, -NHSO ₂ CF ₃ group or -SO ₃ H group or a group selected from the group shown below;

[Chemical 14] Y is a cyano group, a benzyl group, a tosyl group, a methoxymethyl group, an ethoxymethyl group, a methoxyethoxymethyl group or a 1H-tetrazol-5-yl group which may be substituted with a trimethylsilylethoxymethyl group or an alkali metal salt thereof, CO ₂ R ⁷ group, -CONR'R "group, -C
ONHSO ₂ R ⁸ group, amino group, —NHSO ₂ CF ₃ group or —SO ₃ H group; R ² , R ³ , R ⁴ and R ⁵ each independently represent a hydrogen atom or a lower alkyl group; Alternatively, R ² and R ³ , or R ⁴ and R ⁵ may be taken together to form an ═O bond; R ⁶ is a hydrogen atom, a halogen atom, a lower alkyl group, a —CF ₃ group or a —CF ₂ C
F ₃ group; R ⁷ is a hydrogen atom, an alkali metal atom or a lower alkyl group; R ′ and R ″ are each independently a hydrogen atom or a lower alkyl group, or R ′ and R ″
May together form an alicyclic structure; R ⁸ is a lower alkyl group, a cycloalkyl group or an aryl group; R ⁹ is a lower alkyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group, aryl group, or an aryloxy group; R ^10, R ¹¹ and R ¹² are each, independently, a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a cyano group, -CO ₂ R ⁷ group or - CO
NR'R "group; R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸
Are each independently a hydrogen atom, a lower alkyl group, a lower fluoroalkyl group, -C (R ') (R ")-OR ¹⁹ group,-
_{(CH 2) j-CO 2} R 7 _{group, - (CH 2) j-} CN group, - (C
_{H 2) j-C (=} O) R ' _{group, - (CH 2) j-} CONR'R " group, or - represents a (CH ₂₎ j-Aryl groups, here, j is 0, 1 or 2, Here, R ¹⁶ and R ¹⁸ together form-(C
H ₂ ) i-group may be formed, wherein i is 1, 2 or 3, and Aryl is substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a nitro group or a cyano group. May be, phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, tenyl group, pyrazolyl group, oxazolyl group, thiazolyl group,
An oxadiazolyl group or an isoxazolyl group; R ¹⁹ represents a hydrogen atom, or a lower alkyl group which may be substituted with a hydroxy group or an ether group] is reacted with a diimide (HN = NH) to give a C ring diamine. By selectively reducing the heavy bond, the general formula (II):

[Chemical 15] [Wherein R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , R ¹⁴ ,
R < ¹⁵ >, R < ¹⁶ >, R < ¹⁷ > and R < ¹⁸ > are the same as defined above] and provide a process for producing an imidazole derivative or a pharmaceutically acceptable ester or salt thereof.

First, variable substituents used in the general formulas of the compounds described in the present specification will be explained.

The lower alkyl group represented by R ¹ is
An alkyl group having 1 to 8 carbon atoms, for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl,
t-butyl, n-pentyl, isoamyl, n-hexyl, n
-Heptyl, n-octyl and the like. The lower alkoxy group represented by R ¹ is methoxy, ethoxy, n
—Propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isoamyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like. Examples of the lower alkylthio group represented by R ¹ include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio and the like. Examples of the lower alkylamino group represented by R ¹ include methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di (n-
Propyl) amino, isopropylamino, n-butylamino, n-pentylamino, pyrrolidino, piperidino,
Examples thereof include piperazino and morpholino. The lower alkenyl group represented by R ¹ includes vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned. The lower alkynyl group represented by R ¹ includes an acetylene group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,
2-pentynyl, 1-hexynyl, 1-heptynyl, 1
-Octynyl and the like. The aryl group and aralkyl group represented by R ¹ include those having 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like. These aryl groups or aralkyl groups are
If desired, it may be substituted with a lower alkyl group as described above, or a substituent such as a lower alkoxy group, a halogen atom, a nitro group or a cyano group.

When R is a substituted or unsubstituted phenylmethyl group, the halogen atom defined by X ¹ , X ² and X ³ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and Examples of the lower alkyl group and lower alkoxy group include the lower alkyl group and alkoxy group defined above. X ¹ , X ² and X ³ are 1
When it is an H-tetrazol-5-yl group, examples of the alkali metal salt thereof include sodium salt, potassium salt and the like. When X ¹ , X ² and X ³ are a —CO ₂ R ⁷ group, examples of R ^{7 in} the group include a hydrogen atom, an alkali metal atom such as lithium, sodium and potassium, an alcohol having a lower alkyl group as defined above. Examples thereof include ester groups. When X ¹ , X ² and X ³ are -CONR'R "groups, examples of -NR'R" in the groups include amino, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, Di (n-propyl)
Amino, diisopropylamino, dibutylamino, pyrrolidyl, piperazino, morpholino and the like can be mentioned. Further, as an example of R ⁸ in the —CONHSO ₂ R ⁸ group,
Methyl, trifluoromethyl, ethyl, n-propyl, n
-Butyl, isobutyl, t-butyl, cyclopentyl,
Examples thereof include cyclohexyl and phenyl. The groups in which X ¹ , X ² and X ³ are:

[Chemical 16] When it is a group selected from Y and R ⁷ are the same as defined above. The lower alkyl group and lower alkoxy group defined by R ⁹ are the same as defined above. When R ⁹ is a cycloalkyl group or a cycloalkoxy group, it represents a 5- to 7-membered ring compound such as cyclopentyl, cyclohexyl or cycloheptyl. Examples of the aryl group and aryloxy group represented by R ⁹ include substituted or unsubstituted phenyl compounds such as phenyl, p-hydroxyphenyl, p-carboxyphenyl and o-nitrophenyl.
Examples of the case where R ¹⁰ , R ¹¹ and R ¹² are a lower alkyl group, a lower alkoxy group, a —CO ₂ R ⁷ group or a —CONR′R ″ group include those defined above. When it is a biphenylmethyl group, examples of the alkali metal salt of 1H-tetrazol-5-yl as the substituent Y include sodium salt, potassium salt, etc. Further, Y is a —CO ₂ R ⁷ group, —CONR. 'R' group or -CO
In the case of NHSO ₂ R ⁸ groups, R ⁷ in those groups,
-NR'R "and R ⁸ are as defined above. In addition,
R is the following formula:

[Chemical 17] , A halogen atom represented by R ⁶ , an example of a lower alkyl group, Y is an example of an alkali metal salt of 1H-tetrazol-5-yl, Y is a —CO ₂ R ⁷ group, —CONR′R ″
Group or R ⁷ or NR ′ represented by a —CONHSO ₂ R ⁸ group
Examples of R ″ and R ⁸ are as defined above.

When R ² , R ³ , R ⁴ and R ⁵ are lower alkyl groups, examples thereof include alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and n-. Butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like can be mentioned.

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸
Is a lower alkyl group, examples thereof include an alkyl group having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, Examples include n-hexyl, n-heptyl, n-octyl and the like. Also, R ¹³ , R
^{When 14} , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are lower fluoroalkyl groups, examples thereof include trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like. In addition, R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ ,
R ¹⁷ and R ¹⁸ is _{- (CH 2) j-CO} 2 R 7, - (CH 2) j-
C (= O) R ', - C (R') (R ") - OR 19, - (CH 2) j-
And CONR'R ", R ⁷ and R'in those groups are
And R "are as defined above.

Next, the diimide used in the production method of the present invention is
For example, it can be generated by various methods such as oxidation of hydrazine, decomposition of azodicarboxylic acid dipotassium salt with acid, decomposition of arylsulfohydrazide with base and hydroxylamine-acetic acid ester method (Organic Reactions). , 40,
91-155 (1991)). Above all, the operation is simple,
From the viewpoint of high safety, a method utilizing decomposition of p-toluenesulfohydrazide with sodium acetate is preferable.

The reaction between the diimide and the compound of the general formula (I) proceeds efficiently under heating at room temperature to 120 ° C.
The reaction is carried out in a solvent, and examples of the solvent include alcohol solvents such as methanol, ethanol and propanol or ether solvents such as tetrahydrofuran and dimethoxyethane. When p-toluenesulfohydrazide is used as a method for generating a diimide, it is preferable to react with the compound of the general formula (I) while refluxing in dimethoxyethane to generate a diimide.

By this reaction, 10 to 60% of the ring-opened product was conventionally produced as a by-product, but a reduced product of the C-ring double bond was obtained quantitatively without producing a by-product. To be

When R is a protecting group such as a benzyl group, the reduction of the C ring double bond by this method is followed by a conventional method.
Deprotection reaction such as debenzylation can be easily achieved by reacting in methanol in the presence of a catalytic amount of 20% palladium hydroxide-carbon in a hydrogen atmosphere at 1 to 3 atm. Therefore, the production method of the present invention is also useful as a production method of the synthetic intermediate (4) (see the above reaction route). Further, according to the method described in Japanese Patent Application No. 3-277537, Japanese Patent Application No. 3-323474, Japanese Patent Application No. 4-095191 and Japanese Patent Application No. 4-216809, a biphenyltetrazole moiety is bound to this intermediate to form a secondary compound. The imidazole derivative (5), which is the final object, can be obtained as a crystal with almost no product (see the above reaction route). Therefore, it was found that purification by column chromatography, which was indispensable in the conventional method, becomes unnecessary and can be applied with good reproducibility even in mass synthesis.

The compound produced by the process of the present invention can be converted into its ester or salt according to a conventional method, if desired. Such esters or salts include non-toxic pharmacologically acceptable ones, and preferred esters include linear or branched lower alcohol esters such as methanol and ethanol, Preferable salts include alkali metal or alkaline earth metal salts such as sodium salt and potassium salt, hydrohalide salts such as hydrofluoric acid salts and hydrochloride salts, inorganic acid salts such as nitrate salts and sulfate salts, and methane sulfone salt. Examples thereof include lower alkyl sulfonates such as acids, maleates, organic salts such as fumarate, and amino acid salts such as aspartate.

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following examples. Example 1 Formula:

[Chemical 18] 1-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-5,6,7,8-tetrahydro-1 represented by
Synthesis of H-1,3,4a, 8a-tetraaza-cyclopentanaphthalene-4,9-dione 1-benzyl-2-n-butyl-5,8-dimethyl-5,
8-Ethano-5,8-dihydro-1H-1,3,4a, 8a-
Tetraaza-cyclopentanaphthalene-4,9-dione
(58 g, 0.14 mol) and p-toluenesulfonyl hydrazide (187 g, 1.0 mol) were added to dimethoxyethane (400 ml).
And was heated to reflux. Sodium acetate in this solution
An aqueous solution (400 ml) of (165 g, 2.0 mol) was added dropwise over 4 hours. After allowing to cool to room temperature, it was further cooled to 0 ° C., and the precipitated crystals were collected by filtration. The crystals were dissolved in methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Similar procedure (1-benzyl-2-n-butyl-5,8-dimethyl-5,8-ethano-
5,8-dihydro-1H-1,3,4a, 8a-tetraaza-
Cyclopentanaphthalene-4,9-dione (56.5 g) was combined with the residue obtained by silica gel column chromatography (acetone: hexane: methylene chloride = 5: 1: 40) to remove impurities derived from the reagent. Purify with to give the title compound (105 g, 91%) as a colorless solid. In this diimide reduction, only the title compound could be obtained as a single product, and no by-product generated in the reduction with palladium hydroxide was observed. The nuclear magnetic resonance spectrum of this product is as follows.

¹ H-NMR (CDCl ₃ ) δppm: 0.84
(3H, t, J = 7.3Hz), 1.25-1.38 (2H, m),
1.63-1.80 (6H, m), 1.82 (3H, s), 1.89
(3H, s), 2.13-2.24 (4H, m), 2.65 (2H, m)
t, J = 8.0Hz), 5.69 (2H, s), 7.09-7.15
(2H, m), 7.24-7.36 (3H, m)

Example 2 Formula:

[Chemical 19] 2-n-butyl-5,8-dimethyl-5,8-
Ethano-5,6,7,8-tetrahydro-1H-1,3,4
a, 8a-Tetraaza-cyclopentanaphthalene-4,9-
Synthesis of dione 1-benzyl-2-n-butyl-5,8-dimethyl-5,
8-ethano-5,6,7,8-tetrahydro-1H-1,
3,4a, 8a-Tetraaza-cyclopentanaphthalene-
4,9-dione (53 g, 0.13 mol) was added to methanol (30 g).
0 ml) -dissolved in methylene chloride (80 ml). To this solution was added 20% palladium hydroxide (50% water content, 10 g),
The mixture was stirred under a hydrogen atmosphere at 3 atm and room temperature for 4 hours. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol-toluene and the solvent was evaporated under reduced pressure. By repeating this operation 3 times, the title compound (41.1 g, 1
00%) as a colorless solid. The nuclear magnetic resonance spectrum of this product is as follows.

¹ H-NMR (CDCl ₃ + CD ₃ OD) δpp
m: 0.97 (3H, t, J = 7.2Hz), 1.34-1.49
(2H, m), 1.80-1.94 (6H, m), 1.86 (6H, m)
s), 2.10-2.21 (4H, m), 3.17 (2H, t, J =
7.4Hz)

[0024]

INDUSTRIAL APPLICABILITY The process of the present invention provides a method for selectively reducing the C ring double bond of an imidazole derivative having a hydrazine bridged structure, which provides a high yield even in a large-scale synthesis and a more complicated purification step. It became possible to produce a useful imidazole derivative without the need for

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location A61K 31/50 ADM (C07D 487/14 233: 00 237: 00) (72) Inventor Mikio Taniguchi Ibaraki 668-34 Shimohirooka, Tsukuba, Japan (72) Inventor Yoshiji Fujita 6-8-6-302 Namiki, Abiko, Chiba

Claims (3)

[Claims] 1. A general formula: [Wherein R ¹ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a lower alkenyl group, a —CF ₃ group, an aryl group or an aralkyl group; R is a hydrogen atom, or A group selected from the group shown; Here, X is —CH ₂ —, —NR′—, an oxygen atom or —
S (O) _n - represents, here, R 'is a hydrogen atom or a lower alkyl group, here, n represents 0, 1 or 2; here, X ^1,
X ² and X ³ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group,
Cyano group, 1H-tetrazol-5-yl group or alkali metal salts thereof, -CO ₂ R ⁷ group, -CONR'R "group,
-CONHSO ₂ R ⁸ group, amino group, -NHSO ₂ CF ₃ group or -SO ₃ H group, or a group selected from the following group; Y is a cyano group, a benzyl group, a tosyl group, a methoxymethyl group, an ethoxymethyl group, a methoxyethoxymethyl group or a 1H-tetrazol-5-yl group which may be substituted with a trimethylsilylethoxymethyl group or an alkali metal salt thereof, CO ₂ R ⁷ group, -CONR'R "group,-
Or R ^2, R ^3, R ⁴ and R ⁵ are each, independently, represent a hydrogen atom or a lower alkyl group; CONHSO ₂ R ⁸ group, an amino group, -NHSO ₂ CF ₃ group or -SO ₃ H group Alternatively, R ² and R ³ , or R ⁴ and R ⁵ may be taken together to form an ═O bond; R ⁶ is a hydrogen atom, a halogen atom, a lower alkyl group, a —CF ₃ group or a —CF ₂
CF ₃ group; R ⁷ is a hydrogen atom, an alkali metal atom or a lower alkyl group; R ′ and R ″ each independently represent a hydrogen atom or a lower alkyl group, or R ′ and R ″ are together. May form an alicyclic structure; R ⁸ is a lower alkyl group, a cycloalkyl group or an aryl group;
R ⁹ is a lower alkyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group, an aryl group or an aryloxy group; R ¹⁰ , R ¹¹ and R ¹² are each independently a hydrogen atom, a halogen atom or a lower alkyl group. Group, lower alkoxy group, nitro group, cyano group, -CO ₂ R ⁷ group or -CONR'R "group; R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently , A hydrogen atom, a lower alkyl group, a lower fluoroalkyl group, —C (R ′) (R ″) — OR ¹⁹
_{Group, - (CH 2) j-} CO 2 R 7 _{group, - (CH 2) j-} CN group, -
_{(CH 2) j-C (} = O) R ' _{group, - (CH 2) j-} CONR'R "
Or a-(CH ₂ ) j-Aryl group, wherein j is 0,
1 or 2, where R ¹⁶ and R ¹⁸ are taken together-
A (CH ₂ ) i-group may be formed, wherein i is 1, 2 or 3, where Aryl is a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a nitro group or a cyano group. It may be substituted, phenyl group, pyridyl group, pyrimidyl group, pyridazinyl group, furyl group, tenyl group, pyrazolyl group, oxazolyl group, thiazolyl group,
An oxadiazolyl group or an isoxazolyl group; R ¹⁹ represents a hydrogen atom, or a lower alkyl group which may be substituted with a hydroxy group or an ether group], and a diimide (HN = NH) is reacted with the compound. General formula; [Wherein R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , R ¹⁴ and R
¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same as defined above], or a method for producing an imidazole derivative or a pharmaceutically acceptable ester or salt thereof. 2. A general formula: [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ and R ¹⁷ are the same as defined above], and a compound represented by the diimide (HN = N
H) is reacted and then hydrogenolysis is performed. General formula: [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ and R ¹⁷ are the same as defined above] or a pharmaceutically acceptable ester or salt thereof. 3. A general formula: [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , R ¹⁷ and Y
Is the same as the above definition] in the diimide (HN =
General formula characterized by reacting NH): [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹³ , R ¹⁷ and Y
Is the same as the above definition] and a method for producing an imidazole derivative or a pharmaceutically acceptable ester or salt thereof.